Nanoparticles for the potential treatment of Alzheimer’s disease: A physiopathological approach

Nicolás Navarro Martínez; Jorge Toledo Hernández; Javier O. Morales

doi:10.1515/ntrev-2022-0548

Article Open Access

Nanoparticles for the potential treatment of Alzheimer’s disease: A physiopathological approach

Nicolás Navarro Martínez , Jorge Toledo Hernández and Javier O. Morales

Published/Copyright: June 12, 2023

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From the journal Nanotechnology Reviews Volume 12 Issue 1

Abstract

Alzheimer’s disease (AD) is a multifactorial neurodegenerative central system disease with a high prevalence among the elderly and is the most common form of dementia. Oxidative stress is crucial on AD pathogenesis and leads to deposition of neurofibrillary tangles and Aβ plaques; therefore, the use of natural antioxidants or ROS scavengers could help avoid the formation of these aggregates. Similarly, Aβ-degrading/anti-aggregating molecules could help arrest AD progression. Otherwise, traditional anti-Alzheimer drugs such as acetylcholinesterase inhibitors help improve memory and attention deficits. Nevertheless, all these drugs are extensively metabolized, have low plasma concentration, and cannot cross the blood–brain barrier freely. This review discusses different strategies for nanocarrier conjugation of these drugs for brain targeting and delivery, and new approaches on AD treatment according to the most accepted hypotheses of AD pathogenesis. Although none of the existent compounds or drugs can completely arrest the disease’s progression, nanocarrier development of anti-Alzheimer drugs could help delaying the initial or late stages of neurodegeneration. The discovery of new and more complex nanosystems with multiple approaches in AD treatment is needed and will be the next step in AD treatment in the near future.

Keywords: Alzheimer’s disease; nanocarriers; antioxidants; metal scavengers; anti-Aβ; acetylcholinesterase inhibitors

Abbreviations

Ach: acetylcholine
AChEI: acetylcholinesterase inhibitors
AD: Alzheimer’s disease
AGEs: advanced glycation end products
APOE4: ε4 allele of apolipoprotein E
APP: amyloid precursor protein
Aβ: amyloid-beta
BACE1: β-site amyloid precursor protein cleaving enzyme 1
BBB: blood–brain barrier
BChE: butyrylcholinesterase
CaN: calcineurin
CuGly: copper glycinate
MAPK: mitogen-activated protein kinase
Myd88: myeloid differentiation primary response 88
NFATc: nuclear factor of activated T cell c
NFT: neurofibrillary tangles
NMDAR: N-methyl-d-aspartate receptor
NPs: nanoparticles
NSAIDs: nonsteroidal anti-inflammatory drugs
ORAI 1–3: Ca²⁺ release-activated Ca²⁺ channel protein 1–3
PEG: poly(ethylene-glycol)
PKC: protein kinase C
PLGA: poly(lactic-co-glycolic acid)
PSEN1/2: presenilin ½
RAGE: receptor for advanced glycation end products
RNS: reactive nitrogen species
ROS: reactive oxygen species
SLN: solid lipid nanoparticles
STIM1: stromal interaction molecule 1
TAO1/2: thousand and one amino acid protein kinase ½
TLR: toll-like receptor

1 Introduction

Alzheimer’s disease (AD) is a neurodegenerative central system disease with a high prevalence among the older people and is the most common form of dementia. In 2005, 24.2 million people had dementia worldwide, and approximately 70% of the cases were associated with AD [1]. In 2018, Patterson reported that this number increased to 50 million worldwide, and it is expected to reach 152 million in 2050 [2]. AD affects memory, thought, and language processes; in the early phase, short- and medium-term memory is affected, and patients have problems executing complex activities; in the middle phase, the patient is unable to remember for specific periods, impairing their communication, and they experience disorientation on the familiar environment; on the late phase, memory, language, and thought processes are impaired, and AD patients are unable to execute basic activities [3].

The neurobiological mechanism of AD has been extensively discussed over the years [4]; the main hypotheses that explain this pathology are (i) amyloid-beta (Aβ) deposition, (ii) neurofibrillary tangles (NFT) formation, (iii) Ca²⁺ homeostasis dysregulation, (iv) cholinergic axis dysfunction, and (v) oxidative stress-related Aβ and NFT deposition. AD is considered a mixed proteinopathy with the deposition of amyloid and Tau protein [5]. Aβ deposition is one of the more accepted hypotheses that explain familial AD, mutations in the genes encoding amyloid precursor protein (APP), ε4 allele of apolipoprotein E (APOE₄), and presenilin 1/2 (PSEN1/2) result in aberrant Aβ monomer and Aβ fibril production [6,7,8] and as a result, Aβ aggregation, leading to neuronal death and dementia. PSEN mutation increases the levels of Aβ₄₂ or Aβ₄₃, in addition to Aβ₄₀, amyloid fibrils, and predisposes patients to AD onset [9,10,11]. Tau proteins stabilize the microtubule under normal conditions; hyperphosphorylation and cleavage of these proteins lead to their accumulation, aggregation, and neuronal toxicity [12].

Multiple factors contribute to Ca²⁺ homeostasis dysregulation. Ca²⁺ release from the endoplasmic reticulum (through InsP3 and ryanodine) is caused by mutations on presenilin; the increased cytosolic Ca²⁺ levels activate APP protein phosphorylation and, in consequence, increased production of Aβ₄₂ and Aβ oligomers, which leads to the release of Ca²⁺ from the endoplasmic reticulum and memory impairment [13]. It has been observed that AD patients have a significant loss of STIM1 in hippocampal neurons, which explains cytosolic Ca²⁺ upregulation [14].

Cholinergic neurons within the nucleus basalis and septal diagonal band complex are important in memory and attentional function [15]. A severe loss of cholinergic neurons of the basal forebrain in the late stages of AD has been observed; this atrophy is associated with normal aging and is aggravated in patients with mild cognitive impairment and AD [16]. Aβ deposition is strongly correlated with the loss of cholinergic neurons on the basal forebrain; Aβ plaques were observed in postmortem studies of cognitively unimpaired patients [17]. In the early stages of AD, basal forebrain dysfunction could be explained due to dystrophic shrinkage and dysfunction of cholinergic neurons rather than cholinergic neuron loss [18].

Patients with AD and mild cognitive impairment show higher levels of lipid peroxidation metabolites in the brain and reduced levels of glutathione peroxidase and superoxide dismutase [19]. Reactive oxygen species (ROS) production damages the cell and organelle membranes and forms intermediates with proteins by reacting with metals, N− and C− [20]. Oxidative stress on neurons can increase the production of Aβ by increasing APP levels and modulating the activity of BACE-1 and γ-secretase (protease that cleaves APP to produce Aβ), the elevated levels of Aβ oligomers induce Tau protein phosphorylation and NFT formation [21].

AD treatment needs drugs that can cross the blood–brain barrier (BBB), which is not easy. More than 98% of the small lipophilic molecules do not cross the BBB via lipid-mediated free diffusion; these molecules have to weigh less than 400 Da and have less than 8–10 hydrogen bonds [22]. Traditional drugs used on AD have low bioavailability, limited transport, and high brain clearance [23]. The International Organization for Standardization defines nanoparticles (NPs) as particles in the nanometric scale of 1–100 nm [24]; they can be different materials such as polymeric, lipidic, and inorganic and can be used as drug carriers. These nanocarriers can target the brain and surpass the BBB due to their size, surface potential, surface coatings, and conjugation with proteins or antibodies [25] and can cross the BBB by receptor-mediated transcytosis, carrier-mediated transcytosis, adsorptive-mediated transcytosis, or paracellular diffusion [26,27]. This review discusses different strategies for nanocarrier conjugation for brain targeting and delivery of traditional and non-traditional therapies for AD according to the principal hypotheses of AD pathogenesis.

2 NPs across the BBB

The BBB is a semi-permeable barrier formed by microvascular endothelial cells, supported by astrocytes, pericytes, neurons, and the basement membrane [28]. It is responsible for selectively controlling the transport to the brain through the prevention of paracellular diffusion, efflux of hydrophobic substances and drugs, regulating the active transport of nutrients, and transendothelial migration [29]. The NP-assisted delivery of drugs across the BBB must overcome these mechanisms to efficiently accumulate in the brain.

NPs can cross the BBB by active and passive transport that depends on size, charge, and surface modification (Figure 1). Ultra-small NPs (<3 nm) can cross the BBB by paracellular diffusion, while larger NPs (<200 nm) are transported by transcytosis [30,31]. Organic NPs (such as liposomes, PLGA, PLA, and nano-lipids, among others) can be modified for BBB receptor targeting. For example, lactoferrin, insulin, and transferrin receptors are overexpressed on the BBB endothelial cells, and surface modification with their ligands has been successfully used for drug delivery to the brain in vitro [32,33,34]. Another strategy for NP transport across the BBB is targeting carrier proteins. GLUT1 is highly expressed on the BBB endothelial cells, and so mannose and glucose surface modification can be used as targeting ligands [35,36].

Figure 1

Schematic diagram of the NP-mediated anti-Alzheimer drug delivery across the BBB. From left to right, the first NP represents the coating with the receptor (IR, TfR, or LDLR) ligand, the second one represents a glucose- or mannose-coated NP, the third one represents a positively charged gold NP, and the last one represents an ultra-small gold NP. RMT: receptor-mediated transcytosis; CMT: carrier-mediated transcytosis; AMT: adsorptive-mediated transcytosis; IR: insulin receptor, TfR: transferrin receptor; LDLR: low-density lipoprotein receptor; GLUT1; glucose transporter 1.

The luminal side of the BBB is highly negatively charged due to the endothelial cells having a rich phospholipid membrane covered by a glycocalyx formed by negatively charged heparan sulfate proteoglycans [37]. Positively charged NPs interact with the negatively charged surface of the endothelial cells of the BBB, triggering their internalization. The conjugation of NPs with cationic proteins and polymers, such as cationic bovine serum albumin, avidin, and wheat germen agglutinin, among others, has shown evidence of vesicular transcytosis in vitro and in vivo [38,39,40].

3 Applications of nanotechnology on AD

3.1 Antioxidant molecules for neuroprotection in AD

Oxidative stress is one of the primary mechanisms whereby AD produces and perpetuates neuronal damage; antioxidant molecules play a crucial role in the prevention, possible treatment, and arresting AD progression. The activation of stress triggers the protein kinase pathway SAPK/JNK and enables Aβ deposition, lipid peroxidation, and upregulates BACE-1 overexpression, which increases Aβ peptide levels and neuronal death (Figure 2) [41,42,43,44]. At the same time, Aβ deposition activates the JNK/p38 pathway, consequently, mitogen-activated protein kinase (MAPK), which leads to tau hyperphosphorylation and NFT accumulation, causing neuronal damage (Figure 2) [45,46].

Figure 2

Diagram of the neuronal damage and neuronal apoptosis pathways. ORAI 1-3: Ca²⁺ release-activated Ca²⁺ Channel Protein 1-3, STIM1: stromal interaction molecule 1, NMDAR: N-methyl-d-aspartate receptor, TLR: toll-like receptor, Myd88: myeloid differentiation primary response 88, RAGE: receptor for AGEs, CaN: calcineurin, NFATc: nuclear factor of activated T cell c, PKC: protein kinase C, TAO1/2: thousand and one amino acid protein kinase 1/2.

Advanced glycation end products (AGEs) are glycated proteins or lipids produced by pathologies like diabetes and brain aging [47]. AGEs interact with the receptor for AGEs (RAGE) and activate JNK/p38 pathway, enhancing the pro-inflammatory response [48], oxidative stress, and, consequently, Aβ deposition [49,50,51].

Aβ plaque deposition can seize Ca²⁺ in the cytosol, and its polarity change decreases the endogenous levels of GSH over accumulating ROS inside the neurons, causing long-term oxidative stress [52]. Aβ oligomers activate N-methyl-d-aspartate-type glutamate receptors (NMDARs), which increase the Ca²⁺ influx, boosting the accumulation of ROS and reactive nitrogen species [53,54]. Mitochondrial dysfunction can also alter Ca²⁺ homeostasis, ROS deregulation, decreased ATP production, and stress signaling [52]. The change in the cytosolic Ca²⁺ levels activates the enzyme calcineurin [55], which activates Bcl-2 associated death promoter (BAD), releasing cytochrome C from the mitochondria and promoting caspase activation leading to proapoptotic signaling [56,57].

Due to Aβ deposition, glial cells produce pro-inflammatory cytokines, cyclooxygenase, chemokines, and increasing ROS levels and cellular toxicity [58]. Aβ peptides can activate the NADPH oxidase of glia, producing free radicals like superoxide radicals and hydrogen peroxide [59].

3.1.1 Molecular mechanism of natural antioxidants in neurodegeneration

Natural antioxidants exert neuroprotective activity by reducing ROS stress, acting as scavengers of divalent metal ions (Fe²⁺, Zn²⁺, Cu²⁺), disrupting Aβ plaques, and reducing tau tangle formation [60]. These compounds also present anti-neuroinflammatory properties by inhibiting NF-kB and MAPK signaling pathways (Figure 2) [61]. In addition, these molecules modulate the Nrf2/ARE pathway (Figure 3) and inhibit the Keap1 involved in the partial and selective autophagy, reducing oxidative stress and neuroinflammation [62]. Keap1 targets Nrf2 for ubiquitination and proteasome degradation under normal conditions; the oxidative stress-induced environment inactivates Keap1, and Nrf2 binds to ARE, which induces the expression of heme oxygenase-1 (HO-1) gene, superoxide dismutase, and catalase [63,64].

Figure 3

Diagram showing the Nrf2/Keap1/ARE pathway involved on the prevention of AD neurodegeneration by natural antioxidant molecules carried by NPs. ARE: antioxidant response element; GCR: G protein-coupled receptors; Keap1: kelch-like ECH-associated protein-1; Nrf2: nuclear factor erythroid related factor 2; RTK: receptor tyrosine kinase.

The pharmacological use of natural antioxidants for AD prevention and treatment is an attractive alternative to conventional drugs due to their relative safety and efficacy. However, their low absorption, poor bioavailability, rapid metabolism, and excretion limited their use. Orally administered polyphenols are extensively metabolized into glucuronide and sulfoglucuronide in the intestine and liver; these are the main metabolites in plasma [65]. These molecules have low brain uptake ranging from approximately 8 to 166 ng/g [66,67,68,69]. Nanoencapsulation of natural antioxidants is a strategy used to surpass these problems, protecting them from enzymatic metabolization on the gastrointestinal tract, liver uptake, and plasma concentration, and enabling brain targeting.

3.1.2 Nanoencapsulation of natural antioxidant molecules

Natural antioxidants have been widely discussed in recent years for neuroprotection of AD due to their lipophilicity and capacity to transverse the BBB in vitro. Langasco et al. [70] synthesized transfersomes loaded with genistein, a highly lipophilic flavonoid (Table 1), to improve the delivery of genistein by the nose-to-brain route. Transfersomes have many properties, including deformability, size, and in vitro permeation, making them suitable for intranasal administration. This formulation attenuated the ROS overproduction induced by oxidative stress compared to genistein alone and improved the cellular internalization of genistein. Thus, this formulation could be an efficient delivery system of genistein and other highly lipophilic flavonoids by the olfactory nerve pathway.

Table 1

Summary of research on natural antioxidant molecules used for AD

Class	Antioxidant	Log P	Obtained	Ref.
Flavonoids	Genistein	3.04	Soy	[54]
	Quercetin	1.81	Capparis spinosa	[57]
	Hesperetin	2.60	Oranges	[58]
	Curcumin	3.62	Curcuma longa	[61]
	Curcumin	3.62	Curcuma longa	[62]
Fatty acid	Punicic acid	6.4	Pomegranate seed oil	[66]
Stilbene	Resveratrol	2.57	Grapes	[69]

Other natural flavonoids with lower lipophilicity, such as quercetin, have shown functional neuroprotective potential, although they cannot cross the BBB freely. One strategy of nanoencapsulation for flavonoids delivery is the PEGylation of the surface of the NPs, avoiding non-specific binding to proteins and macrophages and, at the same time, increasing their systemic circulation time by evading their aggregation opsonization and phagocytosis [71].

In late stages of AD, the neurotoxic role of glial cells is not clear; overactivation of microglia by cytokines release promotes Aβ accumulation in the brain; at the same time, Aβ activates astrocytes that trigger neuronal death through ROS production [72]. Nday et al. [73] synthesized quercetin-loaded PEGylated silica NPs and compared them to quercetin-loaded cetyltrimethylammonium bromide (CTAB) silica NPs for enhanced quercetin delivery to the brain. The PEGylated NPs in concentrations of 30 or 150 μM improved glial cell viability against 10 or 50 μM copper glycinate (CuGly) on in vitro primary hippocampal cultures; the CTAB NPs did not protect glial cells efficiently from CuGly in any concentration. Avoiding glial ROS production could help reduce the inflammatory response and neurotoxic effect of Aβ accumulation on the brain.

Another strategy to deliver flavonoids is reducing powder particle size to the nanometric scale; this could improve the BBB’s penetration due to the natural lipophilicity of flavonoids. Kheradmand et al. [74] synthesized hesperetin nanocrystals; nano-hesperetin showed better results than hesperetin at 10 and 20 mg/kg, administered by oral gavage on the streptozotocin-induced AD rats in vivo model. The rats treated with nano-hesperetin showed improved memory and learning; decreased lipid peroxidation of the hippocampal area; and increased GSH level, glutathione peroxidase, superoxide dismutase, and catalase activity.

Curcumin is one of the leading natural antioxidant molecules studied in recent years for AD due to its antioxidant, anti-inflammatory, anti-amyloid, and anti-Tau hyperphosphorylation neuroprotective capabilities [75,76]. Despite these findings, curcumin has low gastrointestinal absorption and has the smallest brain uptake of all flavonoids in mice (8.2 ± 1.8 ng/g) [68]. Huo et al. [77] synthesized selenium NP-loaded curcumin/PLGA composites using transgenic 5XFAD mice to exhibit plaques; this material can cross the BBB entirely and bounded to amyloid Aβ plaques.

Kuo and Lin [78] synthesized liposomes with cardiolipin (CL) and wheat germ agglutinin (WGA) loaded with curcumin and nerve growth factor (NGF), CL was used to stabilize the bilayer structure in liposomes and favored the ligand binding of liposomes to Aβ_1–42 in HBMEC-cells and human astrocyte culture cells, observing an increase in permeability of the nanosystem compared to curcumin alone. Also, an increased neuroprotective effect on SK-N-MC cells compared to curcumin alone was shown. The authors also assessed the antiphosphorylation activity on SK-N-MC cells [79]; a reduction in phosphorylated p38 and phosphorylated JNK levels and decreased phosphorylated tau expression protein were observed.

Polyunsaturated fatty acids, such as punicic acid, have shown antioxidant and neuroprotective attributes due to free radical scavenging properties [80,81]. Mizrahi et al. [82] synthesized water-soluble pomegranate seed oil nanoemulsions, containing punicic acid as an antioxidant molecule flavonoids and anthocyanins. In TgMHu2ME199K mice, a model for Creutzfeldt–Jakob disease, these nanoemulsions reduced neuronal death, lipid oxidation, and increased neurogenesis.

Other natural polyphenols, for example, stilbenes, have also shown antioxidant and neuroprotective properties for potential use on AD [83,84]. Loureiro et al. [85] synthesized solid lipid nanoparticles (SLN) containing resveratrol and grape seed and grape skin extracts. They were functionalized with OX26, a monoclonal antibody that binds to cells expressing the transferrin receptors in BBB, mediating their internalization. The SLN containing resveratrol and extracts of grape skin inhibit Aβ_(1–42) (a more neurotoxic residue) [86] fibril formation in 26 and 31%, respectively, when compared to the control. Additionally, the SLN functionalized with the OX26 antibody increases the SLN uptake by BBB cells compared with the LB509 antibody, which recognizes α-synuclein, a protein that is non-specific to the BBB (2-fold higher) or without antibody (fourfold higher). On the other hand, Sun et al. [87] synthesized mesoporous nano-selenium based on the borneol target, β-cyclodextrin nanovalves with loaded resveratrol. Borneol has a transient and rapid BBB-opening effect that could enhance the penetration of nanocarriers [88]. This nanosystem had an encapsulation efficiency of >70% and found that resveratrol release was H₂O₂ concentration dependent. SHSY5Y and bend3 cell lines showed a cell viability of >90% when incubated with 200 µg/mL of the nanosystem. Also, a reduction in ROS and NO levels on SHSY5Y cells treated with Aβ was observed. Finally, the nanosystem could penetrate and release resveratrol on an in vitro BBB model formed by bEnd.3 and SHSY5Y-cells.

Natural antioxidant molecules are being extensively studied nowadays due to their neuroprotective and neurorestorative properties. Due to its lipophilicity and chemical structure, reducing the particle size of highly lipophilic flavonoids could enhance their BBB uptake. Conventional nanocarriers (e.g., SLN, nanoemulsion, nanoethosomes, polymeric NPs) are also alternatives. However, the selection of polymers and materials is restricted by the physiological conditions of BBB uptake and chemical compatibility. These natural compounds have a hormetic biphasic dose–response characterized by low-dose stimulation and high-dose inhibition [89,90]. It is necessary to study this low dose-dependent effect associated with the microdosing of natural antioxidants encapsulated with NPs according to the modulation of the Nrf2/ARE/Keap1 pathway.

3.1.3 ROS/metal scavengers

Metal dyshomeostasis is another hypothesis that explains AD pathogenesis; this theory involves metal ion dysregulation (Zn(ii), Cu(i)/(ii), and Fe(ii)/(iii)), which interacts with Aβ monomers and, in consequence, cause Aβ aggregation [91,92]. Copper and iron can also induce ROS generation through the Fenton (equations (1) and (2)) and Harber–Weiss (equation (3)) reactions [93,94], causing neuronal damage and apoptosis (Figure 2).

(1) O 2 ⟶ Cu + ⇉ Cu 2 + O 2 ∙ − ⟶ Cu + ⇉ Cu 2 + H 2 O 2 ⟶ Cu + ⇉ Cu 2 + OH ∙ ,

(2) O 2 ⟶ Fe 2 + ⇉ Fe 3 + O 2 ∙ − ⟶ Fe 2 + ⇉ Fe 3 + H 2 O 2 ⟶ Fe 2 + ⇉ Fe 3 + OH ∙ ,

(3) O 2 ∙ − + H 2 O 2 ⟶ O 2 + OH ∙ + OH − .

Chelation of these metal ions and ROS products could help avoid Aβ aggregation, Kwon et al. [95] synthesized 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino (polyethylene glycol)-2000] ceria (TPP-ceria) (CeO₂) NPs. TPP-ceria NPs can scavenge mitochondrial ROS, reducing oxidative stress and mitigating the reactive gliosis suppressing cytotoxicity shown in the 5XFAD mouse model. On the other hand, Liu et al. [96] synthesized a prototype NP-chelator conjugate (Nano-N2PY); these polystyrene NPs were functionalized with 2-methyl-N-(2′-aminoethyl)-3-hydroxyl-4-pyridinone. Nano-N2PY showed cellular protection from Aβ cytotoxicity on HCN-1A cells compared with cells treated with Aβ alone. Also, nano-N2PY inhibits Aβ aggregates’ formation in vitro due to their ability to chelate metal ions that formed the aggregates. Notwithstanding the chelation of metal ions and ROS products could help avoid Aβ aggregation, p38/JNK, and SAPK/JNK pathways and, consequently, the pro-inflammatory response cascade remains “activated” causing neuronal damage (Figure 2), the use of nanochelators as carriers of natural antioxidants could help improve the response observed in vitro and in vivo studies shown in this section.

3.2 Aβ degrading/anti-aggregating molecules

Another strategy for treating AD is using anti-Aβ molecules for tagging or with amyloid degrading properties. Agyare et al. [97] developed chitosan polymeric core nanocarriers labeled with a polyamine-modified F(‘ab’) portion of IgG4.1, an anti-amyloid antibody for Aβ tagging in vivo. This formulation accumulated over time in the brain of wild-type (B6/SJL) mice. The uptake of the NPs was higher than the controls on bovine brain microvascular endothelial cells in vitro assay, suggesting the transcytosis of the NPs at the BBB.

Nattokinase is an enzyme capable of degrading amyloid fibrils, suppressing β amyloid and BACE-1 activity; it has shown a recovery of impaired learning and memory capability in vivo and in vitro [98]. Bhatt et al. [99] formulated the PLGA NP-delivery system of the Tet1-conjugated nattokinase enzyme. Tet1 can retrograde transport to neuronal cells and interact with motor neurons. A complete degradation of Aβ₄₀ amyloid plaques was observed after 24 h of digestion.

Another strategy for reducing these aggregates’ interaction is changing the surface charge of Aβ amyloid fibrils with other proteins and inhibiting their toxicity. Klementieva et al. [100] developed poly(propylene imine) glycodendrimers. An inhibition of Aβ_1–40 aggregation and a complete reduction of Aβ_1–42 toxicity were observed on the SHSY5Y cell line compared to the control. APP/PS1 transgenic mice treated intranasally for 1 month did not improve memory impairment. Metallic NPs with negative surface charge can also interfere with Aβ aggregation; Liao et al. [101] synthesized carboxyl conjugated gold NPs. These NPs interfered with Aβ fibrillation in a concentration-dependent manner and affected the preformed Aβ fibrils. It was observed that BE-2-C cells treated with 1.36 nM gold NPs reduced Aβ fibrils’ toxicity to 16%.

Other molecules could inhibit the formation of Aβ by interfering with the synthetic pathways of the fibrils. Sun et al. [102] synthesized immunogenic epitopes (Aβ_1–6, (Aβ_1–6)_2, and Aβ_1–15) on the Aβ C-terminal coupled to protein keyhole limpet hemocyanin or MAP₄. Aβ_1–6-MAP₄ showed the strongest immunogenicity and immunogenic response and reduced the Aβ fiber production by inhibiting the fiber’s formation, and it could depolymerize the previously formed fiber. Also, it was observed that the monoclonal antibody 1H7 specifically recognizes the Aβ₁₋₄₂.

Even though anti-Aβ use seems a viable alternative for AD treatment, it does not address the main problem, which is the formation of Aβ amyloid fibrils and their accumulation on neurons, causing neuronal damage and eventually neuronal apoptosis. It has been reported that Aβ has a biphasic hormetic dose–response, improving the GABAergic connectivity at 20 nM and at 800 nM have the opposite effect on mouse hippocampal neurons [103]. Modulating the hormetic response of the anti-Aβ and antioxidant drugs could be an excellent alternative to regulate the accumulation of sub-toxic concentrations of Aβ and their protective cellular response.

3.3 Acetylcholinesterase inhibitors (AChEI)

AChEI is the primary medication used nowadays for treating dementia associated with AD. Acetylcholinesterase (AChE) is an enzyme that hydrolyzed acetylcholine (ACh) neurotransmitters into acetate and choline; in AD, the loss of neurons is one of the significant symptoms; the loss of neurons on the basal forebrain nuclei results in a reduction of ACh levels [104]. Although in AD patients the ACh receptor system remains unaltered, restoring normal ACh levels could improve neuropsychiatric symptoms [105], which is difficult to achieve because these molecules present low BBB penetration and poor tolerability due to peripheral cholinergic effects. Therefore, nanovehiculization of these drugs could help overcome these problems.

Tacrine was the first AChEI drug approved for the treatment of AD; it was discontinued in 2013 due to safety issues associated with a high incidence of cholinergic peripheral adverse effects and hepatotoxicity; although it is a potent AChE and butyrylcholinesterase (BChE) inhibitor, the use of nanocarriers could help avoid unwanted peripheral effects and reduce hepatotoxicity [106]. Luppi et al. [107] synthesized bovine serum albumin NPs carrying β-cyclodextrins loaded with tacrine. A 100% permeability and a low release rate of tacrine were observed on sheep intranasal mucosa ex vivo assay. It was a suitable option for intranasal delivery of the AChEI drug to the brain, avoiding systemic liberation of tacrine and consumption outside the brain. Joe and Kumar [108] developed PLGA NPs loaded with tacrine. The NPs showed an entrapment efficiency of 81.32% and an in vitro release of about 80% at 24 h on phosphate buffer 7.4. An improvement in cell viability was observed in SHSY5Y cells treated with Aβ at 100 µg/mL.

Galantamine is a slowly reversible dual inhibitor of AChE and BChE (a non-specific esterase) and has acted as an allosteric modulator of nicotinic ACh receptors, which downregulates the central expression of ACh [109]. Galantamine is the best-tolerated AChEI drug with a low incidence of peripheral cholinergic adverse effects [110] compared to rivastigmine and donepezil. However, due to its poor lipophilicity, it is unable to transverse the BBB efficiently. Fornaguera et al. [111] synthesized galantamine-loaded PLGA NPs; this formulation inhibited 80% AChE activity and was not toxic at 0.3 mg/mL on SH-SY5Y cells. In another investigation, Woo et al. [112] synthesized galantamine hydrobromide-loaded Carbopol gel drug reservoirs as a transdermal patch delivery system, showing a sustained galantamine release, reaching almost 69% (maximum concentration of 29 mg/mL, approximately) after 8 h, being higher than the recommended concentration at a dose of 5 mg/kg in rabbits.

Donepezil is a highly specific AChE inhibitor with similar clinical efficacy and limitations of galantamine, such as low BBB penetration, peripheral cholinergic adverse effects, and gastrointestinal intolerance [113]. AnjiReddy and Karpagam [114] developed donepezil-loaded chitosan nanofibers films for oral disintegration. The drug association was about 99%, and about 80% of the drug was released to the medium after 6 min in the in vitro dissolution assay. Almost 100% was released after 60 min in the in vivo drug plasma release assay. A 44.1% A549 cell viability was observed when incubated with 150 µg/mL of the formulation. Other authors, like Jakki et al. [115], synthesized mango gum/chitosan loaded with donepezil NPs and oil/water mango gum loaded with donepezil nanoemulsion. The formulations were nontoxic on SK-N-SK cells at 10–80 µg/mL. Biodistribution studies were performed on Wistar rats; a higher concentration of drugs was observed in the brain, 102.34 ng/mL for NPs and 312.09 ng/mL for the nanoemulsion compared to the pure drug 25.97 ng/mL. Concluding that mango gum extract could be used as a suitable anionic polymer for brain delivery due to its nontoxic and nonirritant properties.

Huperzine A is a highly specific reversible AChEI; Meng et al. [116] synthesized lactoferrin-conjugated N-trimethylated chitosan surface-modified PLGA loaded with huperzine A for intranasal delivery. The NPs were not cytotoxic on 16HBE cells at concentrations lesser than 10 mg/mL and were taken up into the cytoplasm of 16HBE and SH-SY5Y cells in vivo. Kunming mice study showed that the nanosystem was highly distributed in the brain.

In an alternative approach, Roumiani and Dorosti [117] postulated that organophosphates and phosphoramides display inhibitory activities against AChE and BChE; the authors synthesized nanodandelion tin(iv) complex with carbacylamidophosphate (Sn(CH₃)2Cl₂{NC₅H₄C(O)NHP(O)[NHC₆H₁₁]₂}₂). An inhibition constant (IC₅₀) of 326.59 µg/mL was determined, although it was 1.1–1.5-fold higher on BChE than AChE.

AChEI drugs are the primary treatment for AD patients nowadays; these drugs present higher doses tolerance problems, mainly due to peripheral cholinergic adverse effects (i.e., nausea, vomiting, drowsiness, and shakiness) and low BBB penetration. The use of nanocarriers could help improve these problems. However, clearance by the spleen and the liver should be considered, especially on the drugs with reported hepatotoxicity.

3.4 New drugs for AD treatment

New drugs have been assessed for potential AD treatment; for example, Jojo et al. [118] developed lipidic nanocarriers loaded with pioglitazone, a PPARy agonist that activates PI3/Akt and downregulates p38 MAPK pathways reducing oxidative stress, reducing Aβ plaques and NFT formation and neuroinflammation. A 45% drug release was observed at 24 h, with no intranasal ciliotoxicity on sheep intranasal mucosa assay and a good permeation on the Franz diffusion cell assay.

RNA interference technology is one strategy for inhibiting protein synthesis, such as key enzymes for AD progression. Wang et al. [119] synthesized PEGylated poly[2-(dimethylamino)ethyl methacrylate] ethyl methacrylate (PEG-PDMAEMA) modified with CGN peptide and Tet1 for siRNA against β-site amyloid precursor protein cleaving enzyme 1 (BACE1). The nanocomplex did not cause red blood cell aggregation, morphological changes, or ionic interactions with them. Also, the nanocomplexes internalized onto bEnd.3 cells and neuronal cells by the endosomal route showed in vivo targeting of AD lesions neurons and high brain biodistribution after 1 h (>2% dose/g-brain). Finally, the nanocomplexes could effectively silence the BACE1 gene in PC12 cells and in vivo on ICR mice, reduce the production of Aβ plaques and adequately protect neuron, and restore impaired neurogenesis.

Vinpocetine is a phosphodiesterase inhibitor with neuroprotective activities reducing neuroinflammation by inhibiting the IκB kinase complex, impeding the expression of pro-inflammatory mediators [120,121], and improving memory impairment by reducing oxidative stress and modulation of cholinergic function [122]. Moghaddam et al. [123] synthesized nanoethosomes loaded with vinpocetine for transdermal delivery. Nanoethosomes are lipid carriers composed of ethanol, phospholipids, and water. The optimized formulation of nanoethosomes showed a 98.55% entrapment efficiency of vinpocetine, a vesicle size of 44.47 nm, and a transdermal flux across rat skin of 959.63 μg/cm²/h; these findings suggest that this formulation could be used as a functional transdermal delivery system for vinpocetine.

The development of new non-conventional drugs for AD treatment with inhibition of different AD pathogenesis pathways has shown promissory results; nevertheless, more clinical data are required to shed light on drug safety and biodistribution.

3.5 Nonsteroidal anti-inflammatory drugs (NSAIDs) for AD treatment

In response to Aβ plaques and NFT accumulation, microglia infiltration occurs; Aβ plaques activate the TLR of microglia, releasing pro-inflammatory cytokines and chemokines, leading to sustained neuroinflammation [124]. Some authors have discussed NSAIDs used for AD treatment due to the inflammatory imbalance in AD pathogenesis. For example, Al-Azzawi et al. [125] used dendrimeric poly(epsilon-lysine) loaded with flurbiprofen delivery systems. Flurbiprofen is an NSAID with notorious γ-secretase modulation by interacting with presenilin, thus decreasing Aβ₄₂ secretion. The formulation did not affect bEnd.3 cell viability at concentrations up to 400 μM and an increase of 12–14% penetration across the BBB was observed in the bEnd.3 in vitro model compared to free drug. The potential use of dendrimeric carriers to deliver flurbiprofen could improve its low BBB penetration. Other authors, such as Muntimadugu et al. [126], synthesized PLGA and SLN loaded with tarenflurbil (enantiomer of flurbiprofen), a selective Aβ₄₂ lowering agent and y-secretase modulator. The formulation had an entrapment efficiency of 62.31% at 10% drug loading for PLGA NPs and an entrapment efficiency of 57.81% at 10% drug loading for SLNs. After intranasal administration, complete drug release was observed at 2 h from both NPs and high brain biodistribution.

The use of NSAIDs for AD treatment has been controversial due to the partiality of the results; studies have concluded that there is no difference in the reduction of AD risk between NSAIDs users and non-users [127], De Craen et al. [128] have indicated that the beneficial results of NSAIDs might result from recall bias, prescription bias, and publication bias.

4 Detection and diagnosis of Aβ plaques

Kaushik et al. [129] discussed new techniques to detect Aβ plaques in the early and late AD stages and the progressive formation of senile plaques and NFT. Current diagnosis techniques include in vivo imaging (MRI, SPECT, PET, among others) and the patient’s clinical history; different authors have developed different chemical compounds with fluorescent properties and different micro and nanocarriers to deliver them to the brain. Matsumura et al. [130] synthesized various radio-iodinated phenyldiazenyl benzothiazole derivatives as probes for NFT autoradiography and fluorescent staining assays. A high affinity for NFT was observed on in vitro autoradiography and fluorescent assays; however, these derivatives displayed persistent radioactivity in the brain, making them unsuitable for in vivo imaging.

Modified quantum dots for in vivo imaging have been synthesized by Feng et al. [131]. ZnS-capped CdSe quantum dots conjugated with Aβ antibody showed adequate distribution on the brain and targeted the Aβ_1–42 residue on both in vivo and ex vivo assays.

Nevertheless, these conventional techniques are expensive and require a qualified team to operate them. Micro and nanostructured biosensors are new materials that can detect Aβ plaques at the pM level [129] for rapid diagnosis and monitoring of AD patients; however, these devices are limited for clinical uses due to a lack of detection and data on in vivo studies.

5 Toxic effects of NP-based therapies

The most common toxic effects observed in different inorganic nanosystems are neuroinflammation, oxidative stress, induced apoptosis, and autophagy [132]. Sharma et al. reported that aluminum, copper, and silver NPs (50–60 nm) induce BBB disruption and brain edema formation and lead to abnormal cell reactions in Sprague Dawley rats; the NPs were administered by intravenous (30 mg/kg), intraperitoneal (50 mg/kg), or intracerebral (20 μg/10 μL) injections [133]. Even more, Ma et al. [134] observed increased accumulation of titanium in the brain of CD-1 mice after the intraperitoneal injection of nanoparticulate anatase TiO₂ (5 nm) (5, 10, 50, 100, and 150 mg/kg) and bulk TiO₂ (150 mg/kg) daily for 14 days. Neuronal change into filamentous shapes and inflammatory cells was also observed.

On the other hand, Hu and Hammarlund-Udenaes [131] discussed the relevance of increasing the unbound brain-to-plasma partition coefficient (K _p,uu,brain) to enhance brain targeting instead of increasing the transport of the nanosystem to the brain in its intact form, which could enhance the toxic effects of the nanomaterial. Accordingly, receptor-mediated endocytosis of NPs could enhance the cytotoxicity effects of the nanomaterial by the degradation of the receptor/NP complex on the endosomal–lysosomal system and could produce an early release of the drug and accumulation on the cytoplasm (drug-related cytotoxicity) [135].

5.1 Pharmacokinetics of NPs

In general, NPs improve the pharmacokinetic (PK) characteristics of drugs and reduce their peripherical adverse effects [136]. Nevertheless, there is a lack of studies on PK characteristics of the different nanosystems in vivo. It has been discussed that NPs between 10 and 12 nm have high permeation and low accumulation on tissues, while NPs with a hydrodynamic radius <5.5 nm are excreted by the renal route and larger NPs by the liver [137,138]. The surface charge also plays a key role in the biodistribution; NPs coated with nonionic polymers show increased circulation time and opsonization, while positively charged NPs have increased cellular uptake [139,140,141,142]. The clearance of larger and cationic NPs is influenced by the interaction with the mononuclear phagocytic system and reticuloendothelial system, which accumulates the NPs in the spleen and liver. The activation of these systems could trigger an immune response and increase cytotoxic by secretion of tumor necrosis factors, interleukins, and interferons [143].

6 Concluding remarks

AD is a multifactorial neurodegenerative disorder involving several neurobiological mechanisms related to each other. Aβ deposition and NFT formation are the most accepted hypotheses of AD pathogenesis; Ca²⁺ dyshomeostasis, oxidative stress, and neuroinflammation lead to increased production of Aβ₄₂ and Aβ oligomers and tau hyperphosphorylation. Using drugs with antioxidant and anti-neuroinflammatory properties could prevent AD progression and Aβ and NFT production. Natural antioxidants such as flavonoids can inhibit neuroinflammation and have shown strong antioxidant activity, neuroprotective properties, and radical scavenging abilities (hesperetin). In addition, the modulation of the Nrf2/ARE/Keap1 route by the antioxidant molecules could enhance the protection against neurodegeneration associated with oxidative stress. Using other drugs such NSAIDs, ROS/metal scavengers, and Aβ degrading enzymes have shown partial results due to their inability to completely inhibit the cascade of Aβ and NFT production (Figure 2). Modulating the hormetic dose response of these drugs through nanoencapsulation could be a more efficient strategy to achieve neuron protection in early stages of AD.

Another strategy is using AchEI in the early stages of AD treatment to limit neurodegeneration; the cholinergic axis dysfunction contributes to memory and attention deficits observed in AD patients. These compounds have increased brain clearance, poorly penetrate the BBB, and have tolerance problems due to peripheral cholinergic effects; using nanocarriers could help improve brain delivery and may reduce the unwanted side effects.

The physicochemical properties of these compounds made them suitable candidates for lipophilic nanocarrier development for brain delivery (nanoemulsion, nanoethosomes, SLN, etc.); the surface conjugation of these nanosystems with antibodies or polymers can be an excellent strategy to target the BBB receptors and transporters specifically, although the chemical compatibility restricts the selection of these polymers with BBB, which should not increase the size of the NP considerably nor change the surface charge.

The development of more complex nanosystems and the nanovehiculization of multiple anti-AD drugs are needed to treat AD; these systems must have a multifocal approach according to the cascade of Aβ and NFT aggregate formation. Although none of the existent compounds or drugs can completely arrest the disease’s progression, they can delay the initial or late stages of neurodegeneration (Table 2).

Table 2

NP classification according to AD pathogenesis and physicochemical characterization

Classification	Nanovehicles	Main mechanism	Size (nm)	PdI	ζ-Potential (mV)	EE (%)	Ref.
Transferosomes	Genistein-loaded transferosomes	Antioxidant/neuroprotector	132.8 ± 1.35	0.310 ± 0.029	−8.34 ± 1.34	40.36 ± 0.23	[67]
Silica NPs	Quercetin-loaded CTAB silica NPs, and quercetin loaded PEG silica NPs	Antioxidant/neuroprotector	745.3 ± 22.9	0.21 ± 0.02	30.6 ± 2.6	81.9 ± 5%	[70]
Nanocrystal	Nano-hesperetin	Antioxidant/radical scavenger	NS	NS	NS	NS	[71]
PLGA nanospheres	Selenium NPs encapsulated PLGA nanospheres with curcumin	Antioxidant, anti-inflammatory, anti-amyloid, and anti-Tau hyperphosphorylation	70.5 ± 6	NS	NS	NS	[74]
Liposomes	Liposomes with CL and WGA loaded with curcumin and NGF	Antioxidant, neuroprotector, anti-inflammatory, anti-amyloid, and anti-Tau hyperphosphorylation	110–170	NS	−15	∼60	[75]
Nanoemulsion	O/W pomegranate oil nanoemulsion containing punicic acid	Antioxidant/reduced neuronal death, lipid oxidation, and increased neurogenesis	135 ± 12	NS	NS	NS	[79]
SLN	Resveratrol and grape extract-loaded SLN functionalized with the OX26 antibody	Antioxidant/neuroprotector	254 ± 17	0.23 ± 0.05	−4.0 ± 0.1	95 ± 2	[82]
Selenium NPs	Mesoporous nano-selenium based on the borneol target, β-cyclodextrin nanovalves with loaded resveratrol	Antioxidant/neuroprotector	160	NS	−43.4	88.5 ± 4.98	[84]
Ceria NPs	TPP ceria NPs	Mitochondrial ROS scavengers and suppress neuronal death	22	NS	45	NS	[90]
Nanochelator/polystyrene NPs	Nano-N2PY	Chelation of transition metals/to avoid Aβ aggregation	240	NS	NS	NS	[91]
Polymer NPs	Polymeric core nanocarriers labeled with IgG4.1	Anti-amyloid antibody	221.6 ± 22.5	NS	41.6 ± 2.6	52	[92]
PLGA NPs	PLGA NP-delivery system of the Tet1-conjugated nattokinase enzyme	Degrading amyloid fibrils; suppressing β amyloid and BACE-1 activity	192.5	0.145	NS	88	[94]
Polymer NPs	Poly(propylene imine) glycodendrimers	Aβ anti-aggregating	7.4–8.4	NS	NS	NS	[95]
Metallic NPs	Negatively charged gold NPs	Inhibit the formation of Aβ fibrils	30	NS	−38	NS	[96]
None	Immunogenic epitopes	Immunogenicity and immunogenic response and reduced the Aβ fiber production	NS	NS	NS	NS	[97]
Albumin NPs	BSA NPs carrying β-cyclodextrins loaded with tacrine	AChEI	177.4 ± 18.0	0.257	−10.0 ± 0.9	22.0 ± 0.05	[101]
PLGA NPs	Tacrine loaded poly(lactide-co-glycolide) NPs	AChEI	247–293	NS	NS	72.34–81.32	[102]
PLGA NPs	Galantamine PLGA NPs	AChEI					[105]
None	Galantamine hydrobromide-loaded carbopol gel drug reservoirs	AChEI	NS	NS	NS	NS	[106]
Chitosan nanofilm/nanofiber	Donepezil-loaded chitosan nanofiber films	AChEI	150–250	NS	NS	NS	[108]
Nano-emulsion	Mango gum/chitosan loaded with donepezil NPs and o/w mango gum loaded with donepezil nanoemulsion	AChEI	95.1 ± 1.02	0.26	25.92 ± 1.45	85 ± 2.14	[109]
PLGA NPs	Huperzine A/lactoferrin-conjugated N-trimethylated chitosan PLGA NPs	AChEI	153.2 ± 13.7	0.229 ± 0.078	35.6 ± 5.2	73.8 ± 5.7	[110]
Nanodandelion	Nanodandelion tin(iv)/carbacylamidophosphate	AChE and butyl cholinesterase inhibitor	20–50	NS	NS	NS	[111]
Nanolipid	Lipidic nanocarriers loaded with pioglitazone	PPARy agonist that activates PI3/Akt and downregulates p38 MAPK pathways	211.4 ± 3.54	0.257 ± 0.108	14.9 ± 1.09	70.18 ± 4.5	[112]
siRNA nanocarriers	PEGylated poly[2-(dimethylamino)ethyl methacrylate] ethyl methacrylate (PEG-PDMAEMA) modified with CGN peptide and Tet1 for siRNA	Silence BACE1 gene	70–80	NS	∼10	NS	[113]
Nanoethosomes	Nanoethosomes loaded with vinpocetine	Phosphodiesterase inhibitor	50.57 ± 26.1	NS	NS	86.61 ± 2.9	[117]
Polymer NPs	Dendrimer poly(epsilon-lysine) NPs loaded with flurbiprofen,	Aβ₄₂ selective lowering agent and γ-secretase modulator	NS	NS	NS	NS	[119]
PLGA/SLN	PLGA and SLN loaded with tarenflurbil	Aβ₄₂ selective lowering agent and γ-secretase modulator	133.13 ± 7.82/169.87 ± 10.98	0.21 ± 0.02/0.24 ± 0.04	− 30.25 ± 2.11/− 23.13 ± 2.32	64.11 ± 2.2/57.81 ± 5.3	[120]
Quantum dots	ZnS-capped CdSe quantum dots	Targeting of Aβ_1–42 residue	NS	NS	NS	NS	[131]

PLGA: poly(lactic-co-glycolic acid); PEG: poly(ethyleneglycol); CTAB: cetyltrimethylammonium bromide; O/W: oil water; N2PY: nanoparticle-chelator conjugate; SLN: solid lipid nanoparticles; NS: not shown.

tel: +56 (2)29781620/2978 1632

Funding information: The authors acknowledge the financial support through Regular FONDECYT Project 1231154, ANID/PIA/ACT192144, FONDAP Project 15130011 granted by the Chilean National Agency for Research and Development (ANID) and National Doctoral Scholarship POS_NAC_D_2020_1_164514 granted by the National Research and Innovation Agency of Uruguay (ANII).
Author contributions: J.O.M.: conceptualization, resources, writing – review and editing, visualization, supervision, project administration, funding acquisition. N.N.M.: conceptualization, literature analysis, figure design, writing – original draft, review and edition, visualization. J.T.H.: conceptualization, writing – review and editing, visualization. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Conflict of interest: The authors state no conflict of interest.

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Received: 2022-06-14

Revised: 2023-01-17

Accepted: 2023-04-11

Published Online: 2023-06-12

This work is licensed under the Creative Commons Attribution 4.0 International License.

Articles in the same Issue

https://doi.org/10.1515/ntrev-2022-0548

Keywords for this article

Alzheimer’s disease; nanocarriers; antioxidants; metal scavengers; anti-Aβ; acetylcholinesterase inhibitors

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